Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb.
Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci), whereas Wg signal transduction causes increased stability of Armadillo (Arm/beta-catenin), a possible co-factor for the transcriptional regulator Lef1/TCF. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh- and Wg- responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasome pathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.
Jiang
J
J
Howard Hughes Medical Institute, Department of Genetics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. jj10@columbia.edu
Struhl
G
G
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D051186:Armadillo Domain Proteins; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins; D044783:F-Box Proteins; D019204:GTP-Binding Proteins / Q000737:chemistry; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D019476:Insect Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism; D014921:Wings, Animal / Q000196:embryology; D051155:Wnt1 Protein; D044844:beta-Transducin Repeat-Containing Proteins
C495305:ARM protein, Drosophila; D051186:Armadillo Domain Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D044783:F-Box Proteins; D053823:Hedgehog Proteins; D019476:Insect Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014452:Ubiquitins; D051155:Wnt1 Protein; D044844:beta-Transducin Repeat-Containing Proteins; C092937:ci protein, Drosophila; C110233:slmb protein, Drosophila; C074622:wg protein, Drosophila; C077245:hh protein, Drosophila; D044767:Ubiquitin-Protein Ligases; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins